The immune response-related genomic alterations in patients with malignant melanoma.

Immune checkpoint inhibitors (ICIs) significantly improve the survival outcomes of patients with advanced melanoma. However, response varies among from patient to patient and predictive biomarkers are urgently needed. We integrated mutational profiles from next-generation sequencing (NGS) data and clinicopathologic characteristics of melanoma patients to investigate whether tumor genomic profiling contribute to clinical benefit of ICIs treatment. The majority of genes identified with high mutation frequency have all been reported as well-known immunotherapy-related genes. Thirty-five patients (43.2%) had at least 1 BRAF/RAS/NF1 mutation. The other 46 (56.8%) melanomas without BRAF/RAS/NF1 mutation were classified as Triple-WT. We identified mutational signature 6 (known as associated with defective DNA mismatch repair) among cases in this cohort. Compared to patients with PD-L1 expression (TPS < 1%), patients with PD-L1 expression (TPS ≥ 1%) had significantly higher median progression-free survival (mPFS), but no significantly higher durable clinical benefit (DCB) rate. In contrast, FAT1, ATM, BRCA2, LRP1B, and PBRM1 mutations only occurred frequently in patients with DCB, irrespective of PD-L1 expression status. Our study explored molecular signatures of melanoma patients who respond to ICIs treatment and identified a series of mutated genes that might serve as predictive biomarker for ICIs responses in melanoma.

Different gene alterations in patients with non-small-cell lung cancer between the eastern and southern China.

Geographical differences are conspicuous in lung cancer, and the distinct molecular features of lung tumor between Western patients and Asian patients have been demonstrated. However, the etiology of non-small-cell lung cancer (NSCLC) and the distribution of associated molecular aberrations in China have not been fully elucidated. The mutational profiles of 12 lung cancer-related genes were investigated in 85 patients from eastern China and 88 patients from southern China who had been histologically confirmed NSCLC. Overall, 93.6% (162/173) of tumor samples harbored at least one somatic alteration. The most frequently mutated genes were TP53 (56.1%), EGFR (50.3%), and KRAS (14.5%). We found that EGFR mutated much more frequently (60.0% vs 40.9%, P = 0.012) and TP53 mutations had significantly lower incidence (47.1% vs 64.8%, P = 0.019) in eastern cohort than that in southern cohort. Mutational signature analysis revealed a region-related mutagenesis mechanism characterized by a high prevalence of C to T transitions mainly occurring at CpG dinucleotides in southern patients. This study reveals the difference in the mutational features between NSCLC patients in eastern and southern China. The distinct patterns of gene mutation could provide clues for the mechanism of carcinogenesis of lung cancer, offering opportunities to stratify patients into optimal treatment plans based on genomic profiles.

Investigating the genomic alteration improved the clinical outcome of aged patients with lung carcinoma.

BACKGROUND: Lung carcinoma is a common geriatric disease. The development of genotype-targeted therapies greatly improved the management of lung carcinoma. However, the treatment for old patients can be more complex than that for young individuals. RESULTS: To investigate the benefits of genetic detection for older patients with lung carcinoma, we explored the genomic profiling of 258 patients with more than 55 years using a targeted next generation sequencing, and some of these patients were treated with targeted therapies based on the results of genomic detection. KRAS codon 61 mutations were found in 15.2% KRAS-mutated patients, which tend to be co-existing with other classical activating mutations other than codons 12/13. Acquired EGFR C797S mutations were identified in 2 cases and ERBB2 amplification was identified in 1 case. All these 3 cases developed resistance to EGFR tyrosine kinase inhibitors and showed expected results of their followed therapies. The median progression-free survival and median overall survival of patients treated with molecular targeted therapies were better than those of patients treated with chemoradiotherapy alone. CONCLUSIONS: Our findings revealed the specific genomic profiles of patients older than 55 years with lung carcinoma and suggested that these old patients have been benefit from the genetic detection, which helped identify druggable mutations and distinguish resistance mechanisms.

Combination therapy with afatinib and bevacizumab in an EGFR-mutated non-small cell lung cancer patient with acquired ERBB2 amplification: A case report.

INTRODUCTION: Acquired resistance to reversible EGFR tyrosine kinase inhibitors remains a significant obstacle, and acquired ERBB2 amplification is the most common "bypass" mechanism. For patients with sensitizing EGFR mutation who experience resistance via ERBB2 amplification, no targeted drug has been demonstrated to be effective. PATIENT CONCERNS: A 56-year-old female nonsmoker suffered from left leg paralysis and low back pain. Imaging examination revealed a mass in the anterior segment of the right upper lobe lung and possible multiple metastases in the right hilar, mediastinal lymph nodes, bone metastases, and soft tissue invasion. DIAGNOSIS: Transbronchial lung biopsy revealed a moderately differentiated adenocarcinoma (cT4N2M1c, stage IV). An EGFR exon 19 deletion was identified using amplification refractory mutation system. INTERVENTIONS: After the patient was treated with gefitinib initiation (250 mg/d) for 15 months, the tumor progressed with ERBB2 amplification revealed by next-generation sequencing test. Then, the patient was started on afatinib (40 mg/d) plus bevacizumab (7.5 mg/kg every 3 weeks). OUTCOMES: The combination therapy of afatinib and bevacizumab in this patient was effective with some slight side effects. Computed tomography scans showed the tumor shrinkage and the pleural effusion disappeared in the right lung. The overall survival was 23.5 months. CONCLUSION: To date, there is no targeted therapy approved and demonstrated to be effective for non-small cell lung cancer patients with EGFR sensitizing mutations, and ERBB2 amplification. The effectiveness of combination therapy with afatinib and bevacizumab may provide a new therapeutic option for these patients.

DNA Methylation Haplotype Block Markers Efficiently Discriminate Follicular Thyroid Carcinoma from Follicular Adenoma.

CONTEXT: Follicular thyroid carcinoma (FTC) is the second most common type of thyroid carcinoma and must be pathologically distinguished from benign follicular adenoma (FA). Additionally, the clinical assessment of thyroid tumors with uncertain malignant potential (TT-UMP) demands effective indicators. OBJECTIVE: We aimed to identify discriminating DNA methylation markers between FA and FTC. METHODS: DNA methylation patterns were investigated in 33 FTC and 33 FA samples using reduced representation bisulfite sequencing and methylation haplotype block-based analysis. A prediction model was constructed and validated in an independent cohort of 13 FTC and 13 FA samples. Moreover, 36 TT-UMP samples were assessed using this model. RESULTS: A total of 70 DNA methylation markers, approximately half of which were located within promoters, were identified to be significantly different between the FTC and FA samples. All the Gene Ontology terms enriched among the marker-associated genes were related to "DNA binding," implying that the inactivation of DNA binding played a role in FTC development. A random forest model with an area under the curve of 0.994 was constructed using those markers for discriminating FTC from FA in the validation cohort. When the TT-UMP samples were scored using this model, those with fewer driver mutations also exhibited lower scores. CONCLUSION: An FTC-predicting model was constructed using DNA methylation markers, which distinguished between FA and FTC tissues with a high degree of accuracy. This model can also be used to help determine the potential of malignancy in TT-UMP.

Characterizations of Gene Alterations in Melanoma Patients from Chinese Population.

Melanoma is a human skin malignant tumor with high invasion and poor prognosis. The limited understanding of genomic alterations in melanomas in China impedes the diagnosis and therapeutic strategy selection. We conducted comprehensive genomic profiling of melanomas from 39 primary and metastatic formalin-fixed paraffin-embedded (FFPE) samples from 27 patients in China based on an NGS panel of 223 genes. No significant difference in gene alterations was found between primary and metastasis melanomas. The status of germline mutation, CNV, and somatic mutation in our cohort was quite different from that reported in Western populations. We further delineated the mutation patterns of 4 molecular subgroups (BRAF, RAS, NF1, and Triple-WT) of melanoma in our cohort. BRAF mutations were more frequently identified in melanomas without chromic sun-induced damage (non-CSD), while RAS mutations were more likely observed in acral melanomas. NF1 and Triple-WT subgroups were unbiased between melanomas arising in non-CSD and acral skin. BRAF, RAS, and NF1 mutations were significantly associated with lymph node metastasis or presence of ulceration, implying that these cancer driver genes were independent prognostic factors. In summary, our results suggest that mutational profiles of malignant melanomas in China are significantly different from Western countries, and both gene mutation and amplification play an important role in the development and progression of melanomas.

The complete mitochondrial genome of Oreolalax major (Anura: Megophryidae).

The complete mitochondrial genome of a frog species Oreolalax major is determined. This mitogenome length is 17 431 bp, containing 13 protein-coding genes, two rRNA genes, 23 tRNA genes and a control region (D-loop). Compared with most other vertebrates, this mitogenome appears a tandem duplication of tRNAMet gene. The tRNATrp gene of Oreolalax major translocates from the "WANCY" tRNA cluster to upstream of D-loop. As the first report of the mitogenome sequence from the genus Oreolalax, it will provide fundamental data for further research of phylogeny and biogeography with this genus.

Complete mitochondrial genome of Paramegophrys oshanensis (Amphibia, Anura, Megophryidae).

The complete mitochondrial genome of a stream-dwelling frog species Paramegophrys oshanensis was determined. This mitogenome was 17,747 bp in length, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region (D-loop). The base composition of the light strand was 28.77% A, 29.85% T, 26.26% C, and 15.11% G. Compared with most other vertebrates, this mitogenome has some different features: a non-tandem duplication of tRNA-Met gene (forming tRNA-Met1 and tRNA-Met2 genes), the replacement of tRNA-Trp gene by a 72-bp noncoding region translocated from the cluster of WANCY to the back of Cytb gene, the translocation of tRNA-Val gene from the front of 16S rRNA to the back of tRNA-Met1 gene, and the translocation of tRNA-Pro gene from the front of D-loop region to the front of tRNA-Met2 gene. Three kinds of tandem repeats with size ranging from 71 to 92 bp were detected within D-loop region.

The complete mitochondrial genome of Megophrys shapingensis (Amphibia, Anura, Megophryidae).

The complete mitochondrial genome sequence of the Shaping horned toad Megophrys shapingensis, the first complete mitogenome from the family Megophryidae, was determined. The total length of this complete mitogenome was 17,631 bp, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region (D-loop). The gene arrangement and composition of the mitogenome were similar to those of most amphibians. The base composition on light strand was 28.2% A, 31.5% T, 26.1% C, and 14.3% G. The D-loop region contained 10 copies of 97-bp tandem repeats. The complete mitogenome sequence of M. shapingensis provided fundamental data for resolving phylogenetic and genetic problems related to this species.